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Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
Published on: October 23, 2018
Glutaminolysis activates Rag-mTORC1 signaling
Raúl V Durán1, Wolfgang Oppliger, Aaron M Robitaille
1Biozentrum, University of Basel, 4056 Basel, Switzerland.
Molecular Cell
|July 4, 2012
Summary
Glutamine and leucine activate the mTORC1 pathway by increasing glutaminolysis and alpha-ketoglutarate production. This process is crucial for cell growth and may explain cancer cells
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Amino acids regulate cell growth by activating the conserved kinase TORC1.
- Glutamine plays a key role in cell metabolism and growth control, but its precise mechanism in TORC1 activation is unclear.
- Glutamine is metabolized via glutaminolysis, yielding alpha-ketoglutarate.
Purpose of the Study:
- To define the role of glutamine in mammalian TORC1 (mTORC1) activation.
- To investigate the mechanism by which glutamine and leucine activate mTORC1.
- To explore the link between glutaminolysis, alpha-ketoglutarate, and mTORC1 signaling.
Main Methods:
- Investigated the effect of glutamine and leucine on mTORC1 activation.
- Assessed the impact of inhibiting glutaminolysis on RagB GTP loading and lysosomal translocation.
- Utilized constitutively active Rag heterodimers and alpha-ketoglutarate analogs to study mTORC1 activation.
Main Results:
- Glutamine and leucine co-activate mTORC1 by enhancing glutaminolysis and alpha-ketoglutarate production.
- Inhibition of glutaminolysis blocks RagB GTP loading, lysosomal translocation, and mTORC1 activation.
- Enhanced glutaminolysis or alpha-ketoglutarate analog stimulates mTORC1 activation and lysosomal translocation.
- Cell growth and autophagy, processes regulated by mTORC1, are modulated by glutaminolysis.
Conclusions:
- mTORC1 senses glutamine and leucine through glutaminolysis and alpha-ketoglutarate production upstream of Rag proteins.
- This pathway provides a mechanistic link between amino acid availability and mTORC1 signaling.
- The findings may explain the 'glutamine addiction' observed in cancer cells.
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